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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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[Janus kinase inhibitors].

Torsten Witte1

  • 1Klinik für Rheumatologie und Immunologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland. Witte.torsten@mh-hannover.de.

Zeitschrift Fur Rheumatologie
|November 25, 2021
PubMed
Summary
This summary is machine-generated.

Janus kinase (JAK) inhibitors offer oral administration and pain control for rheumatoid arthritis, but safety concerns regarding malignancies and cardiovascular events require further investigation. Long-term data will determine their place in treatment guidelines.

Keywords:
BaricitinibFilgotinibRheumatoid arthritisTofacitinibUpadacitinib

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Area of Science:

  • Rheumatology
  • Pharmacology
  • Clinical Trials

Background:

  • Janus kinase (JAK) inhibitors were approved for rheumatoid arthritis (RA) treatment starting in 2017.
  • Unlike biologicals, JAK inhibitors target multiple cytokines and offer oral administration.
  • Three of four JAK inhibitors demonstrated superiority over adalimumab in certain endpoints in randomized controlled trials.

Purpose of the Study:

  • To compare the efficacy and safety of Janus kinase (JAK) inhibitors with biological treatments for rheumatoid arthritis.
  • To evaluate the role of JAK inhibitors in the current therapeutic landscape for rheumatoid arthritis.

Main Methods:

  • Review of randomized controlled trials comparing JAK inhibitors to adalimumab.
  • Analysis of data from the Oral Surveillance trial and CorEvitas registry.
  • Evaluation of phase III approval trial safety data.

Main Results:

  • JAK inhibitors showed efficacy in pain control and offered oral administration.
  • Three JAK inhibitors were superior to adalimumab in some randomized controlled trial endpoints.
  • Increased rates of malignancies and major cardiovascular events were observed with tofacitinib in the Oral Surveillance trial, but not in other studies.

Conclusions:

  • JAK inhibitors present an alternative to biologicals for rheumatoid arthritis, with advantages in administration and pain relief.
  • Ongoing safety evaluations and registry data are crucial for defining the optimal use of JAK inhibitors in RA treatment algorithms.
  • Further research is needed to clarify the long-term safety profile and comparative effectiveness of JAK inhibitors.